In parallel with major recent advances in basic immunology, opportunities for clinical exploitation of this understanding have broadened, as has our ability to perform direct assessment of immunological mechanisms in humans. This is a cornerstone of the Immune Tolerance Network (ITN) approach - clinical assessment of novel tolerance therapeutics, while simultaneously evaluating the cellular, genetic and immunologic mechanisms of disease and how they are altered in response to therapy. In this renewal application, we describe the scientific and operational framework that we propose to enable the ITN to successfully accelerate the development of tolerance therapies in transplantation, autoimmunity, and allergy. We will outline a process to evolve our current strategies into the next generation of planned trials, as well as how we plan to operate a nimble, future-focused organization, poised to lead and adopt future innovations that are currently unknown. We propose a collaborative structure involving hundreds of investigators, advisors, and clinical sites working in tandem with a core group of ITN staff, operating a program that is both scientifically and financially efficient. Several new innovations recently adopted by the ITN will encourage widespread involvement from academic investigators, including expanded resource sharing and data sharing operations. Three major institutions, the Benaroya Research Institute at Virginia Mason, Massachusetts General Hospital, and the University of California, San Francisco, form the administrative backbone for this application, with another twenty institutions represented in leadership and major advisory roles. RELEVANCE: The proposed Immune Tolerance Network (ITN) grant addresses major unmet health needs. In the United States, autoimmune diseases affect >5% of the population, and allergic diseases affect another ~15%. Transplantation is a life-saving intervention for organ failure, but it comes with a significant burden and risk, in each area, pre-clinical studies show that immune tolerance should be an achievable therapeutic prospect for many affected individuals. Successful tolerance offers the possibility of long-term freedom from immunosuppressive therapy, bringing a radical improvement in terms of quality of life, disease burden, and health care cost.